P-Alkyl or cycloalkyl phenoxy alkanols and alkanol esters and process for the treatment of allergic conditions

ABSTRACT

p-Alkyl or cycloalkyl phenoxy alkanols and esters are provided having the structure: ##STR1## in which: R 1  is an alkyl group having from one to six carbon atoms, preferably tertiary, and still more preferably tertiary-butyl; or a bivalent cycloalkylene group condensed with the phenyl group at adjacent ring carbons thereof, such as in indane; 
     R 2  is lower alkyl having from one to three carbon atoms or hydrogen; 
     R 3  is hydroxyl or an ester group selected from the group consisting of COOR 4  and OOCR 4  derived from unsubstituted and hydroxy-substituted monocarboxylic acids and COOR 5  OOC and OOCR 5  COO derived from unsubstituted and hydroxy-substituted dicarboxylic acids, the acids being selected from the group consisting of aliphatic acids, including carbamic acid, having from one to about twelve carbon atoms; cycloaliphatic acids having from three to about twelve carbon atoms; carbocyclic aromatic acids having from six to about twenty carbon atoms; and nitrogen heterocyclic aromatic acids having from five to about twelve carbon atoms, R 4  being monovalent aliphatic, cycloaliphatic, aromatic, or nitrogen heterocyclic aromatic, and R 5  being divalent aliphatic, cycloaliphatic, aromatic, or nitrogen heterocyclic aromatic, the acids being esterified with aliphatic alcohols having from one to six carbon atoms; and carbonic acid monoalkyl esters, the alkyl having from one to three carbon atoms; and 
     n 1 , n 2  and n 3  represent the number of CH 2 , C(R 2 ) 2  and CH 2  groups, respectively, and are numbers within the range from 0 to 10; and at least one of n 1 , n 2  and n 3  is other than zero. 
     These compounds inhibit abnormal tissue reactivity due to specific allergic hypersensitivity or due to specific irritants by inhibiting the release of chemical mediators.

This is a division of application Ser. No. 327,141, filed Dec. 3, 1981,now U.S. Pat. No. 4,451,474, which in turn is a continuation-in-part ofSer. No. 114,183, filed Jan. 22, 1980, now abandoned.

A person is said to be allergic when he shows hypersensitivity to asubstance which is harmless to most other people. This hypersensitivitycan manifest itself in many ways, such as, for example, in bronchialasthma, rhinitis, urticaria, eczema, and others. The agent to which theallergic individuals are hypersensitive, i.e., the allergen, stimulatesthe production of specific antibodies. When an allergen comes intocontact with its specific antibody, a number of toxic substances arereleased from the cell, including, among others, histamine, slowreacting substance A, bradikinin, serotonin, leukokinin, kalikrein, andother kinins and prostaglandins. The release of these toxic substancesis responsible for the observed symptoms in all allergic disorders. Thisfield has been reviewed by Kaliner and Austen in Annual Review ofPharmacology 15 177-189 (1975).

Various remedies have been prescribed for the treatment of allergies,but no entirely satifactory treatment is available.

The antihistimines decrease the sensitivity of some but not all tissuesto histamine, but do not affect the sensitivity of tissues to othertoxic substances released during the allergic reaction. Theantihistamines do not affect the release of histamine or other toxicsubstances released during allergic reactions.

Bronchial dilators are used for the symptomatic treatment of asthma, butthey have no specific anti-allergenic action.

Corticosteroids decrease inflammatory reactions when given in largedoses, but their usefulness in treatment is limited by the serious sideeffects that accompany their use.

Some compounds are known that affect allergic reactions by inhibitingmediator release, but none of the known substances is broadly effective,and some have toxic side effects.

Cox, Nature 216 1328 (Dec. 30, 1967) described the activity of a4H-1-benzopyran-2-carboxylic acid derivative he called cromolyn sodiumor disodium cromoglycate. This compound is ineffective when administeredorally, because it is very poorly absorbed from the gastrointestinaltract. For this reason, the compound has to be given by inhalation. Inaddition, it has a relatively low activity, making the administration ofan effective dose impractical. The drug has to be givenprophylactically, as it is ineffective when given therapeutically. Forthese reasons, the compound although known for many years has not beenwidely used.

Chlorphenesin, a p-chlorophenyl glycerol ether, was reported byLichtenstein and Atkinson, The Journal of Immunology 103 866 (1969), toinhibit histamine release from human leukocytes. Previously, thecompound was described by Berger and Bradley, The British Journal ofPharmacology 1 265 (1946) as having a muscle-relaxant action, similar tothat produced by mephenesin, by a depressant effect on the interneuronsof the central nervous system. The antifungal action and antibacterialaction of the compound were described by Bergen, Hubbard and Lugwig,Journal of Applied Microbiology 1 146 (1953).

Berger, Fukui, Goldenbaum, DeAngelo and Chandlee, The Journal ofImmunology 102 1024 (1969) reported the effect of the drug on immuneresponses. Chlorphenesin when given jointly with the antigen suppressedantibody formation. The drug also had an effect on delayedhypersensitivity reactions, when given at the time of challenge.

Chlorphenesin also suppressed passive cutaneous anaphylaxis induced bypenicillin, according to Berger, Fukui, Ludwig and Margolin, Proceedingsof the Society for Experimental Biology and Medicine 124 303 (1967).

Chlorphensin also was reported to inhibit allergen-reagin-inducedhistamine and SRS-A release from monkey lung tissue passively sensitizedwith human reagin, by Malley and Baecher Journal of Immunology 107 586(1971).

Kimura, Inoue and Honda demonstrated that chlorphenesin and cromolynsodium inhibited the degranulation of the rat mast cells mediated byIgE-anti-IgE reaction, and published their findings in Immunology 26 983(1974).

Chlorphenesin also inhibited release of histamine induced byconcanavalin A from basophil cells according to Siraganian andSiraganian, Journal of Immunology 112 2117 (1974).

Stites, Brecher, Schmidt and Berger showed that chlorphenesin inhibitedmitogenic responses of mouse and human B and T cells induced byphytohemagglutinins, lipopolysaccharide or staphylococcal protein A. Thecompound also inhibited the mixed lymphocytes reactions in inbredstrains of mice and in unrelated human (Immunopharmacology In Press(1979).

These results suggest that chlorphenesin has a broad spectrum of effectson the inhibition of release of various mediator substances and that itcan exert its effect without inducing tolerance or affecting antigenicpriming of immuno-competent cells. However chlorphenesin possesses onlya low order of activity and is rapidly metabolized and broken down inthe body rendering its use impractical. The interesting properties ofchlorphenesin stimulated investigation of related compounds.

Inai, Okazaki, Shimada, Kagei and Bessho, U.S. Pat. No. 3,846,480patented Nov. 5, 1974 describe chlorphenesin in succinate and its alkalimetal salts, and indicated that these were much superior tochlorphenesin in their anaphylactic histamine release-preventive effect.These compounds are not being used therapeutically because of inadequateclinical and pharmacological potency.

Reisner, Ludwig, Fukui and Berger U.S. Pat. No. 3,879,544 patented Apr.22, 1975 developed a group of new aryl thioalkanones having the formula:##STR2## wherein X is halogen or lower alkyl; m is an integer 1 or 2 andn is an integer from 2 to 6, inclusive. As used throughout the instantspecification and claims the term lower alkyl shall mean carbon chainscontaining 1-6 carbon atoms.

However, these compounds cause serious side effects, and have a hightoxicity, and are therefore too dangerous to use.

As of 1975 and before, at the time of U.S. Pat. No. 3,879,544, and theearly work on cromolyn sodium and chlorphenesin, it was thought that thesymptoms of allergy were due primarily to the release of histamine. Forthis reason, compounds were only evaluated as to their ability toprevent release of histamine from sensitized cells. However, it is nowrecognized that symptoms of allergy are caused by the release of manyother substances, including slow-reacting substance A(SRSA), serotonin,bradikinin, various prostaglandins, and many other mediators. Thereforethe tests that were used were designed to enable one to determinewhether the compounds of this invention suppress the release from cellsand tissues not only of histamine but also of other mediator substancesreleased during allergic reactions and tissue irritation. One of thesubstances having this property is compound 48/80, as stated by Goodmanand Gillman, The Pharmacological Basis of Therapeutics, Third Edition, p622, the Macmillan Company, New York (1965), now an accepted material inthe test procedure described by Lewis and Whittle, British Journal ofPharmacology 61 229 (1977).

In work unrelated to allergic reactions, Berger and Fukui U.S. Pat. No.3,549,766 patented Dec. 22, 1970 described a method of eliminating orreducing hypersensitivity to penicillin by administering in conjunctionwith the penicillin, certain phenoxy propanols or phenoxypropanediolshaving the structure: ##STR3## wherein X is selected from the groupconsisting of hydrogen, halogen, lower alkyl and lower alkoxy; and R andR₁ are each selected from the group consisting of hydrogen and hydroxyl,at least one being hydroxyl.

As used herein and the appended claims, the terms "lower alkyl" and"lower alkoxy" signify respectively alkyl and alkoxy radicals havingfrom one to about six carbon atoms.

This group includes chlorphenesin, in the case when X is Cl and R and R₁are each OH. Nothing in the patent suggests possible utility of phenoxypropanols or diols in inhibiting abnormal tissue reactivity due tospecific allergic hypersensitivity or due to specific irritants byinhibiting the release of chemical mediators that are responsible forthe symptoms of allergic diseases, and the many symptoms of irritationand inflammation produced by irritants and inflammation-causingsubstances.

In a contemporaneous paper, Berger and Fukui, Giornaledell'Arteriosclerosi V No. 5-Sept-Oct 1967 describe the effect of thephenoxy propanediols in decreasing the penicillin-induced passiveanaphylaxis reaction, with particular emphasis on chlorphenesin,3-p-chlorophenoxy, 1,2-propanediol. In the summary at the end of thepaper, the authors comment:

These observations appear to be of particular interest because the modeof action of these compounds appears to be entirely different from thatof previously described inhibitors of anaphylactic reactions. Thephenoxypropanediols do not destroy penicillin and do not affect itsantibiotic action. They are devoid of antihistaminic andanti-inflammatory properties and do not act by depressing the generalreactivity of the organism. The compounds appear to act by a selectiveblocking of certain antibody sites, thus making the antibody unable toreact with penicillin. This effect is of particular interest because ofits specificity. The action of phenoxypropanediols on cutaneousanaphylaxis may open up new approaches to the treatment ofhypersensitivity and autoimmune diseases.

A corresponding report by Berger, Fukui, Ludwig, and Margolin appearedin Proc. of the Society for Exp. Biology and Medicine 124 303-310(1967), and the same conclusion is reached at page 310.

In accordance with the present invention, a group of compounds areprovided that are related to chlorphenesin but are far more effective ininhibiting mediator release, and are more resistant to inactivation bythe metabolic reaction in the body. They are moreover free from toxic ordeterious side effects. They are in fact from four to twenty times aseffective, milligram for milligram, as chlorphenesin, and from five tofifty as effective, milligram for milligram, as cromolyn sodium, insuppressing the release of mediator substances. They consequentlyrepresent an important break-through in the treatment of allergicconditions, and for the first time permit a practical approach by way ofinhibition of the release of all mediator substances.

The compounds in accordance with the invention are p-alkyl or cycloalkylphenoxy alkanols and esters having the general formula: ##STR4## inwhich: R₁ is an alkyl group having from one to six carbon atoms,preferably tertiary, and still more preferably tertiary-butyl; or abivalent cycloalkylene group condensed with the phenyl ring at twopositions, as in indane;

R₂ is lower alkyl having from one to three carbon atoms or hydrogen;

R₃ is hydroxyl or an ester group selected from the group consisting ofCOOR₄ and OOCR₄ derived from unsubstituted and hydroxy-substitutedmonocarboxylic acids and COOR₅ OOC and OOCR₅ COO derived fromunsubstituted and hydroxy-substituted dicarboxylic acids, the acidsbeing selected from the group consisting of aliphatic acids, includingcarbamic acid, having from one to about twelve carbon atoms;cycloaliphatic acids having from three to about twelve carbon atoms;carbocyclic aromatic acids having from six to about twenty carbon atoms;and nitrogen heterocyclic aromatic acids having from five to abouttwelve carbon atoms, R₄ being monovalent aliphatic, cycloaliphatic,aromatic, or nitrogen heterocyclic aromatic, and R₅ being divalentaliphatic, cycloaliphatic, aromatic, or nitrogen heterocyclic aromatic,the acids being esterified with aliphatic alcohols having from one tosix carbon atoms; and carbonic acid monoalkyl esters, the alkyl havingfrom one to three carbon atoms; and

n₁, n₂ and n₃ represent the number of CH₂, C(R₂)₂ and CH₂ groups,respectively, and are numbers within the range from 0 to 10; and atleast one of n₁, n₂ and n₃ is other than zero.

These compounds differs from the Reisner et al compounds disclosed inU.S. Pat. No. 3,879,544 in being oxy ethers rather than thio ethers.Moreover, in the series of the invention, the p-substituent on thephenoxy group is alkyl or cycloalkylene, and the alkyl, while it can beunbranched, is preferably tertiary, whereas Reisner et al disclosed nobranched chain alkyl groups whatoever. Replacement of thioether byoxyether eliminates the toxic reactions, which thus appear to beassociated with the thio ether group, although this is not referred toin the Reisner et al patent.

These compounds inhibit abnormal tissue reactivity due to specificallergic hypersensitivity or due to specific irritants by inhibiting therelease of chemical mediators that are responsible for the symptoms ofallergic diseases, including allergic rhinitis, asthma, hypersensitivityof the skin and of the gastrointestinal canal, and the many symptoms ofirritation and inflammation produced by irritants andinflammation-causing substances, and prevent rejection of transplantedcells and organs and particularly of bone marrow and insulin-producingLangerhans cells.

The compounds of this invention may also be used to prevent rejection oftransplanted tissues and organs by decreasing and altering the graftversus host and host versus graft reactions. Examples of such a usewould be transplantation of healthy bone marrow to patients sufferingfrom leukemia, or transplantation of insulin-producing pancreaticLangerhans cells to diabetic patients.

The compounds of this invention also prevent the development ofhypersensitivity to substances capable of producing allergic reactionson the skin or elsewhere when administered together with them.

The inhibiting effect of the compounds of the invention in all of theabove types and classes of therapeutic effects is genericallyencompassed herein by the phrase:

"effective to inhibit abnormal tissue reactivity due to specificallergic hypersensitivity or due to specific irritants by inhibiting therelease of chemical mediators that are responsible for the symptoms ofallergic diseases and irritation and inflammation produced by irritantsand inflammation-causing substances"

Exemplary R₁ alkyl substituents include methyl, ethyl, propyl,isopropyl, butyl, secondary-butyl, tertiary-butyl, amyl, secondary-amyl,tertiary-amyl, hexyl, secondary-hexyl, and tertiary-hexyl. Isobutyl hasso far shown itself to be inactive, which is anomalous, and possiblyincorrect.

Exemplary R₁ cyloalkylene substituents include cyclopropylene,cyclobutylene and cyclopentylene, forming five, six and seven memberedcarboxylic rings with the phenyl, as in indane and tetrahydroquinoline.

Exemplary R₂ are methyl, ethyl, propyl and isopropyl.

Exemplary R₃ are, in addition to hydroxy, ester groups OOCR₄ derivedfrom monocarboxylic acids such as carbamic acid, acetic acid, propionicacid, butyric acid, valeric acid, hexoic acid, and hydroxy-substitutedsuch monocarboxylic acids having a carbon:oxygen ratio from 1:1 to notexceeding 2:1, such as glycolic acid, and sugar acids such as glycericacid, erythronic acid, threonic acid, gluconic acid, galactonic acid,mannonic acid, gluconic acid, idonic acid, attronic acid and allonicacid; cyclopropanoic acid, cylobutanoic acid, cyclopentanoic acid,cyclohexanoic acid, cycloheptanoic acid, cyclooctanoic acid, benzoicacid, salicylic acid, m-chlorobenzoic acid, p-chlorobenzoic acid,m-hydroxybenzoic acid, protocatechinic acid, gentisic acid, gallic acid,phenylacetic acid, toluic acids, xylic acids, hydrocinnamic acid,naphthoic acid, α-picolinic acid, isonicotinic acid, nicotinic acid,quinnic acid, quinaldinic acid, cinchroninic acid, acridinemonocarboxylic acid, phenanthridine monocarboxylic acid, pyrimidinemonocarboxylic acid, pyrazine monocarboxylic acid, pyridazinemonocarboxylic acid, triazine monocarboxylic acid; methyl carbonic acid,and ethyl carbonic acid; and ester groups COOR₄ derived from alcoholsand phenols such as methanol, ethanol, propanol, butanol, pentanol,hexanol, phenol, and benzyl alcohol; ester groups OOCR₅ COO derived fromdicarboxylic acids such as oxalic acid, malonic acid, succinic acid,glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid,and sebacic acid; and hydroxy-substitituted dicarboxylic acids in acarbon:oxygen ratio from 1:1 to not exceeding 2:1, such as malic acid,tetrahydroxy adipic acid, mannosaccharic acid, idesaccharic acid,talomucic acid, tartaric acid, trihydroxy glutaric acid, glucuronicacid, galactouronic acid, saccharic acid and mucic acid.

In the preferred compounds, n₁ is a number from 3 to 8, and n₂ and n₃are zero, R₃ is nicotinic acid, and R₁ is tertiary-butyl, tertiary-amyl,or tertiary-hexyl.

A number of preferred compounds falling within the invention areillustrated in Tables I and II.

The compounds of the invention can be made by any of three generalsyntheses: ##STR5##

This is the procedure used in Examples I, III, VI, VII, and IX to XIV.

This route involves in step (a) reaction of a phenol having the R₁substituent of Formula I, page 7, with an ester or acid corresponding instructure to the ##STR6## substituent, having a group X that is suitablyactivated for displacement by a phenoxide ion at the position where thegroup is to be linked to the phenolic hydroxy group. The reactionrequires ionization of the phenolic substrate with a suitable base, suchas an alkali metal hydride, an alkali metal hydroxide, carbonate oralkoxide, or an organic base such as a tertiary amine, for instance,triethyl amine, pyridine, or a quaternary ammonium hydroxide such astetramethyl ammonium hydroxide, in an inert organic solvent, such as apolar solvent. Typical solvents are illustrated in the Examples applyingthis reaction, which follow.

The reaction proceeds at room temperature up to a moderately elevatedtemperature within the range from about 25° to about 150° C.

The COOR group is an ester derived from the acid COOH esterified with analcohol, such as the alkanols, in which case R is an alkyl group, suchas methyl, ethyl, propyl and butyl; an aryl group derived from a phenol,such as phenyl and naphthyl; an alkaryl group derived from an arylalcohol, such as benzyl and phenethyl; and a cycloalkyl group derivedfrom a cycloalkanol, such as cyclohexyl and cycloheptyl.

X represents the activated substituent, and is preferably halogenselected from the group consisting of chlorine, bromine and iodine, butsulfonyloxy groups can also be used.

The n₁, n₂ and n₃ substituents correspond of course to the likesubstituents of Formula I on page 7, as also does the R₁ substituent onthe phenol.

If the desired compound of Formula I has as R₃ an ester group COOR, thenstep (b) of the reaction can be omitted. If the terminal group includingR₃ has the structure CH₂ OH or CH₂ OOCR, the step (b) is used.

In step (b) of this reaction, the phenoxy alkylene ester is reduced witha metal hydride, such as lithium aluminum hydride, diisobutyl aluminumhydride, or other hydrides, or a borane, converting the ester COOR groupto a CH₂ OH group, in the presence of an inert organic solvent that iscompatible with and inert to strong reducing agents. Ethers, such asdiethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane can beused, as well as hydrocarbons such as toluene, which may be favored withthe alkyl metal hydrides.

Then, if the terminal R₃ group is to be CH₂ OOCR, the CH₂ OH group isesterified with an acid RCOOH using conventional esterificationprocedures. ##STR7##

This is the procedure used in Examples II, and XVII to XXII.

In step (a) of this procedure, a phenol ##STR8## having a parasubstituent corresponding to R₁ is employed together with a loweracrylic acid ester, which following reduction in step (b) produces asubstituent corresponding to the ##STR9## substituent of Formula I onpage 7.

The reaction between the phenol and the lower acrylate ester requiresionization of the phenolic substrate with a suitable base, such as ametal hydride, alkali metal hydroxide, carbonate, or alkoxide, or asuitable organic base, as in Synthesis A, but it can also be carried outwith only a catalytic quantity of the base, and in the absence of aninert organic solvent. The R substituent on the acrylic acid can bealkyl, aryl, alkaryl or cycloalkyl, but in this case better yields areobtained when R is of a higher molecular weight than methyl or ethyl,such as, for example, butyl.

The higher acrylate esters have higher boiling points, and it is likely,if the reaction is carried out under reflux, that the higher boilingpoint of the acrylate ester influences the reaction, with the bestyields being obtained when the acrylate ester has a boiling point above100° C.

If the desired compound of Formula I has as R₃ an ester group COOR, thenstep (b) of the reaction can be omitted. If the terminal group includingR₃ has the structure CH₂ OH or CH₂ OOCR, the step (b) is used.

In step (b) of this reaction, the COOR ester group is reduced to CH₂ OH,as in Synthesis A, and a similar procedure can be used.

Then, if the terminal R₃ group is to be CH₂ OOCR, the CH₂ OH group isesterififed with an acid RCOOH using conventionl esterificationprocedures. ##STR10##

This synthesis also requires ionization of the phenolic substrate with asuitable base, preferably in an inert organic solvent as in Synthesis A,followed by alkylation with a suitable halogen-substituted or sulfonateester-substituted alcohol or ester having a structure corresponding tothe ##STR11## group, where OR is R₃ of Formula I on page 7.

The X group is suitably activated for displacement by a phenoxide ion,and can be any of the X groups of the esters in Synthesis A.

In the case where the alkylene substituent has two, four and five carbonatoms, R₃ is preferably an ester group, but in other cases R₃ can beeither hydrogen or an ester group. At the particular chain length wherethe substituent has two, four and five carbon atoms, the cyclization ofthe reagent to ethylene oxide, tetrahydrofuran or tetrahydropyran iscompetitive with alkylation of the phenoxide, reducing the yield, unlessthe hydroxyl group is protected by esterification. Thus, when the numberof carbon atoms in the substituent is two, four or five, the hydroxylgroup should be protected by reaction with an acid, so as to form anester, such as the acetate or propionate, the esterifying radical beingremoved, if the corresponding alkanol is required, by ordinarysaponification following the alkylation. Where an ester is the desiredreaction product, of course the ester moiety can be employed as thereagent.

This reaction proceeds at an elevated temperature within the range fromabout 25° to about 150° C., and is preferably carried out in an inertorganic solvent, preferably a polar solvent.

This synthesis is used in Examples V and XVI.

In all of the Examples the calculated and found values are percent byweight.

EXAMPLE I Preparation of 2-p-t-butylphenoxyethanol

A solution of 10.0 g (66.7 mmoles)p-tertibutylphenol in 50 ml drydimethyl formamide was added, dropwise, to a mechanically stirred slurryof 8.4 g sodium hydride (as 50% oil dispersion)in 500 ml dry dimethylformamide. To the phenoxide solution was added, dropwise, a solution of6.3 g(66.3 mmoles) chloroacetic acid in 50 ml dry dimethyl formamide.The reaction mixture was stirred at room temperature for tow hours. Thereaction mixture was diluted with 200 ml diethyl ether and acidifiedwith 3N hydrochloric acid. The aqueous layer was removed and washed with200 ml diethyl ether. The organic layers were combined, dried (MgSO₄)and evaporated to a white gummy residue which was dried in vacuoyielding p-t-butylphenoxyacetuc acid, 9.0 g (65%).

Analysis: NMR Spectrum (CDCl₃) δ 1.25 (s, 9 H, (CH₃)₃ C--), 4.60##STR12## 7.03 (q, 4 H, --(C₆ H₄)--).

To a stirred solution of 5.2 g (25 mmoles)2-p-tert-butylphenoxy)-aceticacid in 10 ml dry tetrahydrofuran cooled to 0° C. was added, dropwise,45 ml(42 mmoles)0.95 M borane in tetrahydrofuran. After ten minutes at0° C. the solution was stirred at room temperature for one hour. Thereaction mixture was then acidified, pH=2, with 3 N hydrochloric acid,diluted with 50 ml water, and extracted with dichloromethane (2×200 ml).The organic layers were combined, dried and concentrated to a yellow oilwhich was distilled in vacuo (89° C./0.075 mm Hg) to a clear, colorlessoil, 2-p-t-butylphenoxyethanol.

Analysis: NMR Spectrum (CDCl₃) δ 1.28 (s, 9 H, (CH₃)₃ C--), 4.00 (m, 4H, O-(CH₂ CH₂)--OH), 7.10 (q, 4 H, --C₆ H₄ --).

Calculated: C₁₂ H₁₈ O₂ : C, 74.2; H,9.34.

Found C, 74.4; H, 9.59.

EXAMPLE II Preparation of 3-p-t-butyl-phenoxypropanol

A solution of 25 g (0.167 mole) p-tert-butylphenol, 0.2 g sodium hydride(as 50% dispersion in oil), 0.2 g N-phenyl-2-naphthylamine (as basicpolymerization inhibitor) in 75.0 g (0.586 mole ) butyl acrylate washeated at 125° C. for four hours. The temperature was then reduced in100° C. and the excess acrylate distilled under gentle vacuum. Theresulting oil was filtered through 900 g silica gel (90 to 200 mesh)using chloroform as eluant to yield 21.0 g pure butyl3-(p-tert-butylphenoxy)-propionate (45%).

This ester 21.0 g was dissolved in 500 ml dry ether and cooled to -5° C.in an ice/acetone bath. To the cold solution was added, cautiously, aslurry of 3.5 g lithium aluminum hydride in 100 ml dry ether. After onehour the excess lithium aluminum hydride was destroyed by the cautiousaddition of 200 ml ethyl acetate, then 50 ml water. The solution wasfiltered and the filtate partitioned between 200 ml ether - 200 mlwater. The organic layer was removed, dried, and evaporated to a yellowoil which was vacuum distilled (116° C./0.35 mm) over potassiumcarbonate to a clear colorless oil, 3-p-t-butylphenoxypropanol, 10.1 g(64%).

Analysis: NMR Spectrum (CDCl₃) δ 1.31 (s, 9 H, (CH₃)₃ --), 1.95 (m, 2H,--CH₂ (CH₂)CH₂ OH), 3.68 (t, 2 H, --CH₂ (CH₂)OH), 3.95 (t, 2 H,--O(CH₂)CH₂ CHOH), 7.05 (q, 4 H, --(CH₆ H₄)--).

Calculated: C₁₃ H₂₀ O₂ : C, 75.0; H, 9.68.

Found: C, 75.2; H, 9.77.

EXAMPLE III Preparation of 4-p-t-butylphenoxy-1-butanol

Method A. To a stirred slurry of 1.6 g sodium hydride (as 50% dispersionin oil) in 50 ml dry dimethyl formamide was added, dropwise, a solutionof 5.0 g p-tert-butylphenol (33.3 mmoles) in 50 ml dry diemthylformamide and the solution stirred under nitrogen until the phenoxidehad totally formed. To the phenoxide was added a solution of 5.0 g4-chlorobutyl acetate (33.3 mmoles) in 50 ml dry dimethyl formamide andthe solution was stirred for fourteen hours. The reaction mixture waspartitioned between water/ toluene. The organic layer was removed,washed with water, then 1 N sodium bicarbonate. The organic layer wasremoved, dried and evaporated to an orange oil, 5.6g. The oil waschromatographed on 500 g, 90 to 200 mesh silica gel (CH₂ Cl₂ eluent)yielding pure 4-(p-tert-butylphenoxy)-butyl acetate.

Analysis: NMR Spectrum (CDCl₃) δ 1.3 (s, 9 H, (CH₃)₃ C--), 2.00 (s,3 H,(s, 3H, CH₃)₇ 4.40 ##STR13## 7.03 (q,4H, --(C₆ H₄)--).

Calculated C₁₆ H₂₄ O₃ ; C, 72.7; H, 9.15.

Found: C, 73.0; H, 9.16.

Method B. To a stirred solution of 1.1 g, 14.0 mmoles acetyl chloride in50 ml dry dichloromethane was added, dropwise, a solution of 2.0 g, 9.0mmoles, of the alcohol 4-p-t-butylphenoxy-1-butanol, in 25 ml of drydichloromethane. The solution was stirred for sixteen hours, thenquenched with 50 ml water. The organic layer was removed, dried (MgSO₄)and condensed to a yellow oil which was vacuum distilled (122° C./0.35mm Hg) over potassium carbonate to a clear, colorless oil,4-(p-tertbutylphenoxy)-butyl acetate. The NMR spectrum was in agreementwith the NMR spectrum of the acetate ester prepared by Method A.

The acetate ester (24.9 g) was treated with 125 ml, 1 N methanolicpotassium hydroxide at reflux for one hour. The methanol was thenevaporated and the residue partitioned between 300 ml dichloromethaneand 300 ml water. The dichloromethane solution was removed, dried(MgSO₄), and evaporated to a yellow oil which was vacuum distilled (117°C., 0.8 mm) to a clear, colorless oil, 4-p-t-butylphenoxy-1-butanol,19.2 g (92%).

Analysis: NMR Spectrum (CDCl₃) δ 1.27 (s, 9 H, (CH₃)₃ C--), 3.65 (t, 2H,--(CH₂)OH), 3.95 (t,2H, O(CH₂)CH₂ --), 7.05 (q, 4 H, --(C₆ H₄)--).

Calculated: C₁₄ H₂₂ O₂ ; C, 75.6; H, 9.97.

Found: C, 75.6; H, 10.0.

EXAMPLE IV Preparation of 5-p-t-butylphenoxy-1-pentanol

To a stirred slurry of 3.2 g sodium hydride (as 50% dispersion in oil)in 100 ml dry dimethyl formamide was added, dropwise, a solution of 10.0g (66.6 mmoles ) p-tert-butylphenol in 100 ml dry dimethyl formamide andthe solution stirred under nitrogen until the phenoxide had totallyformed. To the phenoxide solution was added a solution of 12.0 g, 0.805mole, 5-bromo-1-pentene in 100 ml dry dimethyl formamide. The reactionmixture was stirred for one hour then partitioned between 500 ml ether -500 ml water. The ether was removed, dried (MgSO₄), and evaporated to ayellow oil which was vacuum distilled (69° C./0.03 mm) to a clear,colorless oil 5-p-t-butylphenoxy-1-pentene, 10.5 g (72.2%).

Analysis: NMR Spectrum (CDCl₃) δ 1.27 (s, 9 H, (CH₃)₃ C--), 3.92 (t, 2H, --O(CH₂), 5.87 (m, 1 H, --(CH)═CH₂), 7.04 (q, 4 H, --C₆ H₄)--).

The 5-(p-tert-butylphenoxy)-1-pentene (10.5 g) was treated with 115 ml0.5 M 9-borabicyclononane in tetrahydrofuran and the reaction mixturewas stirred at reflux for one hour. The solution was cooled to roomtemperature and treated with 25 ml 3 N sodium hydroxide, then 10 ml 30%hydrogen peroxide. After the bubbling ceased the reaction mixture waspartitioned between 150 ml ether -150 ml water. The ether layer wsremoved, dried (MgSO₄), and evaporated to a yellow oil which waschromatographed through 300 g, 90 to 200 mesh silica gel (2% MeOH/CH₂Cl₂ eluent) yielding a yellow oil which was vacuum distilled (126°C./0.75 mm) to a clear, colorless oil, 5-p-t-butylphenoxy-1-pentanol,1.7 g.

Analysis: NMR Spectrum (CDCl₃) δ 1.27 (s, 9 H, (CH₃)₃ C--), 3.63 (t, 2H,--(CH₂)OH), 3.93 (t, 2 H, --(CH₂)OAn), 7.08 (q, 4 H, --(C₆ H₄)--.

Calculated: C₁₅ H₂₄ O₂ ; C, 76.2; H, 10.2.

Found: C, 76.2; H, 10.3.

EXAMPLE V Preparation of 6-p-t-butylphenoxy-1-hexanol

To a stirred slurry of 0.64 g sodium hydride (as 50% dispersion in oil)in 10 ml dry dimethyl formamide was added, dropwise, a solution of 2.0 g(13.3 mmoles) p-tert-butylphenol in 10 ml dry dimethyl formamide. Afterthe phenoxide had totally formed a solution of 1.8 g (13.1 mmoles)6-chloro-1-hexanol in 10 ml dry dimethyl formamide was added and themixture stirred for forty-eight hours. The reaction mixture waspartitioned between 100 ml ether - 100 ml water. The ether was removeddried (MgSO₄), and evaporated to an orange oil. The oil waschromatographed on 200 g 90 to 200 mesh silica gel (2% MeOH/CH₂ Cl₂eluent) to a yellow oil which ws vacuum distilled (136° C./0.25 mm) toafford 0.96 g 6-p-t-butylphenoxy-1-hexanol.

Analysis: NMR Spectrum (CDCl₃) δ 1.30 (s, 9 H, (CH₃)₃ C--), 3.58 (t, 2H, --(CH₂)OH), 3.91 (5, 2 H, --O(CH₂)--CH₂ --), 7.05 (q, 4 H, --(C₆H₄)--).

Calculated: C₁₆ H₂₆ O₂ :C, 76.8; H, 10.5.

Found: C, 76.8; H, 10.4.

EXAMPLE VI Preparation of 8-p-t-butylphenoxy-1-octanol

Methyl 8-bromooctanoate was prepared by treating 8-bromooctanoic acidwith excess thionyl chloride at reflux for two hours. Evaporation of theexcess thionyl chloride and treatment of the acid chloride with excessmethanol yielded the methyl 8-bromooctanoate as a yellow oil. To astirred slurry of 0.64 g sodium hydride (as 50% dispersion in oil) in 10ml dry dimethyl formamide was added, dropwise, a solution of 2.0 g, 13.1mmoles, p-tert-butylphenol in 10 l ml dry dimethyl formamide. After thephenoxide had totally formed, a solution of 3.2 g,(13.3 mmoles),methyl8-bromooctanoate, in 10 ml dry dimethyl formamide was added. Thereaction mixture was stirred at room temperature for sixteen hours thenpartitioned between 100 ml hexane - 100 ml water. The organic layer wasremoved, dried (MgSO₄), and condensed to a yellow oil, methyl8-p-t-butylphenoxyoctanoate, 3.6 g.

Analysis: NMR Spectrum (CDCl₃) δ 2.28 (t, 2 H, --(CH₂)-13 COOCH₃), 3.63##STR14## 3.90 (t, 2 H, O--(CH₂)--CH₂ --), 7.05 (q, 4 H, --C₆ H₄)--).

The ester methyl 8-p-t-butylphenoxyoctanoate, 3,6 g, was dissolved in100 ml dry diethyl ether and added, dropwise, to a stirred slurry of 0.4g lithium aluminum hydride in 200 ml dry diethyl ether. After two hoursthe excess lithium aluminum hydride was quenched with 100 ml distilledwater. The mixture was filtered through Celite. The organic layer wasremoved from the filtrate, dried (MgSO₄), and condensed to a yellow oil,0.9 g, which was vacuum distilled (155° C./0.2 mm) to a clear colorlessoil, 8-p-t-butylphenoxy-1-octanol, 0.7 g.

Analysis: NMR Spectrum (CDCl₃) δ 3.57 (t, 2 H, --(CH₂)OH), 3.91 (t,2 H,--O--(CH₂)CH₂), 7.05 (q, 4 H, --(C₆ H₄)--).

Calculated: C₁₈ H₃₀ O₂ C, 77.7; H, 10.9.

Found: C, 77.5; H, 10.8.

EXAMPLE VII Preparation of 11-t-butylphenoxy-1-undecanol

12.0 g, 48.2 mmoles, 11-bromoundecanoic acid was treated with excessthionyl chloride for two hours at reflux. The excess thionyl chloridewas distilled off. The resulting residue dissolved in dichloromethaneand treated with excess methanol. Evaporation yielded methyl11-bromoundecanoate as an orange oil, 12.1 g. To a stirred slurry of0.64 g sodium hydride (as 50% dispersion in oil) in 10 ml dry dimethylformamide was added, dropwise, a solution of 2.0 g, (13.3mmoles),p-tert-butylphenol in 10 ml dry dimethyl formamide. After thephenoxide had totally formed, a solution of 3.7 g, (13.3 mmoles), ofmethyl 11-bromoundecanoate in 10 ml dry dimethyl formamide was added andthe solution stirred at room temperature under nitrogen for fourteenhours. The reaction mixture was then partitioned between 100 ml hexane -100 ml water. The organic layer was removed, dried (MgSO₄), andcondensed to a yelldow oil, methyl 11-p-t-butylphenoxyundecanoate, 3.7g.

The methyl 11-(p-tert-butylphenoxy)-undecanoate, 3,7 g, 10.6 mmoles, wasdissolved in 100 ml dry diethyl ether and added, dropwise, to a stirredslurry of 0.5 g lithium aluminum hydride in 100 ml dry diethyl ether.After one hour the reaction mixture was filtered through Celite and thefiltrate was treated with 100 ml 1 N hydrochloric acid. The organiclayer was removed, dried (MgSO₄), and concentrated to a yellow oil, 2.7g. The oil was chromatographed on 200 g 90 to 200 mesh silica gel (2%MeOH/CH₂ Cl₂ eluent) collecting the product as a white, waxy solid. Thesolid was recrystallized from warm pentane yielding pure11-(p-tert-butylphenoxy)-undecanol, 1.1 g, m.p. 39° to 40° C.

Analysis: NMR Spectrum (CDCl₃) δ 3.57 (t, 2 H, --(CH₂)OH), 3.89 (t, 2 H,--O--(CH₂)--CH₂ --), 7.05 (q, 4 H, --(C₆ H₄)--).

Calculated: C₂₁ H₃₆ O₂ : C, 78.7; H, 11.3.

Found: C, 78.6; H, 11.3.

EXAMPLE VIII Preparation of 5-p-t-butylphenylpentanol

Methyl 4-crotonyltriphenyl phosphonium bromide 9.2 g (20.9 mmoles) wasdissolved in 500 ml ice water and carefully neutralized with 2% sodiumhydroxide. The resulting precipitate was filtered and dried in vacuoyielding 6.8 g of the phosphorane. The phosphorane, 6.8 g (18.8 mmoles)was suspended in 100 ml methanol and to this was added 3.0 g (18.9mmoles), p-tert-butylbenzaldehyde and the mixture was stirred at roomtemperature for one hour, then at 0° C. for sixteen hours. The productwas collected by filtration to afford 1.4 g methyl5-p-t-butylphenyl-2,4-pentadienoate.

Analysis: NMR Spectrum (CDCl₃) δ 1.33 (s, 9 H, (CH₃)₃ C--), 3.72##STR15##

The olefin,methyl 5-p-t-butylphenyl-2,4-pentadienoate, 1,4 g, wasdissolved in 50 ml methanol and hydrogenated at 1 atmosphere over 5%rhodium on alumina. The reaction mixture was then filtered throughCelite and the filtrate evaporated to a yellow oil, methyl5p-t-butylphenylpentanoate, 1.4 g.

Analysis: NMR Spectrum (CDCl₃) δ 1.30 (s, 9 H, (CH₃)₃ C--), 2.45##STR16## 3.61 ##STR17## 7.18 (q, 4 H,--C₆ H₄ --).

The ester methyl 5-p-t-butylphenylpentanoate 1.4 g was dissolved in 50ml anhydrous ether and added, dropwise, to an ice cold slurry of 200 mglithium aluminum hydride in 50 ml anhydrous ether. After one hour thesolution was filtered through Celite and the filtrate was washed with200 ml 1 N hydrochloric acid. The organic layer was removed, dried(MgSO₄) and concentrated to a yellow oil which was vacuum distilled(134° C./0.75 mm) to a clear, colorless oil 5-p-t-butylphenylpentanol,0.34 g.

Analysis: NMR Spectrum (CDCl₃)δ1.32 (s,9H, (CH₃)₃ C-), 2.58 (t,2H,--C₆H₄₋₋(CH₂)--), 3.59 (t,2H,--(CH₂)OH), 7.18 (q,4H,--C₆ H₄ --).

Calculated: C₁₅ H₂₄ O: C,81.8;H,11.0.

Found: C,81.0;H,10.8.

EXAMPLE IX Preparation of 4-p-t-butylphenoxy-1-butyl benzoate

To a well stirred solution of 2.0 g, 9.0 mmoles, of the alcohol4-p-t-butylphenoxy-1-butanol, and 1.25 ml pyridine in 30 ml benzene wasadded, 1.8 g, 13.4 mmoles, benzoyl chloride in 30 ml benzene, and thesolution stirred under nitrogen for sixteen hours. The reaction mixturewas then filtered and the filtrate washed with 50 ml 1 N hydrochloricacid. The organic layer was removed, dried (MgSO₄) and evaporated to ayellow oil which was vacuum distilled (168° C./0.4 mm) to a clear,colorless oil, 4-p-t-butylphenoxy-1-butyl benzoate, 1.6 g.

Analysis: NMR Spectrum (CDCl₃)δ1.28 (s,9H, (CH₃)₃ C--), 1.95 (m,4H,OCH₂(CH₂ CH₂)CH₂ O), 4.00 ##STR18## 4.40 (t,2H,--C₆ H₄ O(CH₂)--), 7.05(q,4H, --C₆ H₄₋₋), 7.53 (m,3H, benzoyl 3,4,5-H's) 8.08 (m,2H, benzoyl2,6-H's).

Calculated: C₂₁ H₂₆ O₃ : C, 77.3,H, 8.03.

Found: C,76.9; H,7.99.

EXAMPLE X Preparation of methyl 4-p-t-butylphenoxy-1-butylcarbonate

To a well stirred solution of 2.0 g, 9.0 mmoles, of the alcohol4-p-t-butylphenoxy-1-butanol, and 0.8 ml pyridine in 25 mldichloromethane was added 1.6 g (16.8 mmoles) methyl chloroformate in 25ml dichloromethane and the solution was stirred for forty-eight hours.The reaction mixture was then evaporated and the residue chromatographedon 200 g 90 to 200 mesh silica gel (chloroform eluent) yielding 2.8 g ofpale yellow oil. Vacuum distillation (131° C./0.25 mm) rendered theproduct as a clear, colorless oil, methyl4-p-t-butylphenoxy-1-butylcarbonate, 1.5 g.

Analysis: NMR Spectrum (CDCl₃)δ1.26 (s,9H, (CH₃)₃ C--), 1.82 (m,4H,OCH₂(CH₂ CH₂)CH₂ O),3.73 (s,3H,CO(CH₃)), 8.93 ##STR19## 4.18 (t,2H,--C₆ H₄O(CH₂)--), 7.05 (q,4H,--C₆ H₄ --).

Calculated: C₁₆ H₂₄ O₄ : C, 68.5; H, 8.63.

Found: C, 69.3; H, 8.73.

EXAMPLE XI Preparation of 4-p-t-butylphenoxy-1-butyl nicotinate

Nicotinoyl chloride was prepared by treating 100 g (0.81 mole) ofnicotinic acid with 280 ml of thionyl chloride at reflux for two hours.The excess thionyl chloride was removed in vacuo and the crystallineacid chloride hydrochloride was suspended in 500 ml of dichloromethane.To the stirred mixture was added 66 g (0.30 mole) of4-p-t-butylphenoxy-1-butanol dissolved in 400 ml of dichloromethane.After forty-eight hours the mixture was washed with one liter ofsaturated sodium bicarbonate. The dichloromethane solution was driedover magnesium sulfate and evaporated to a syrupy residue. The materialwas chromatographed on 1 kg of silica gel with elution bydichloromethanemethanol, 96:4, to afford 43.8 g (45%) of the nicotinateester as an oil. The hydrobromide salt was prepared by treatment of asolution of 43.8 g in 800 ml of ethyl acetate with 30 ml of 4.5 Nhydrogen bromide in ether. The precipitate was collected, washed withpentane and dried, m.p. 132°-133° C.

Analysis: 15 NMR Spectrum (d₆ DMSO)δ1.30 (s,9H, (CH₃)₃ C--), 1.96(m,4H,OCH₂ (CH₂ CH₂)CH₂ O), 4.05 ##STR20## 4.49 (t,2H,O (CH₂)--CH₂ --),7.09 (q,4H,--C₆ H₄), 8.14 (q,1H,Pyr--5H), 9.01 (q,2H,Pyr--4,6-H's), 9.34(s,1H,Pyr--2H).

Calculated: C₂₀ H₂₅ NO₃.HBr: C, 58.8; H, 6.42; N, 3.43.

Found: C, 59.0; H, 6.43; N, 3.33.

EXAMPLE XII Preparation of 3-p-t-butylphenoxypropanol carbamate

To a stirred slurry of 3.0 g, 14.4 mmoles, of the alcohol3-p-t-butylphenoxy propanol, and 2.5 g potassium cyanate in 50 mlbenzene was added 3.4 g trifluoroacetic acid and the solution wasstirred under nitrogen for two hours. The mixture was then treated with50 ml water. The organic layer was removed, dried (MgSO₄), and condensedto an orange oil. The oil was dissolved in 25 ml pentane and stored at0° C. The crystals were filtered and dried in vacuo yielding 0.9 g ofthe urethane, m.p. 84° to 85° C.

Analysis: NMR Spectrum (CDCl₃)δ1.32 (s,9H, (CH₃)₃ C--), 2.08(m,2H,O--CH₂ (CH₂)CH₂ O--), 4.02 ##STR21## 4.24 (t,2H,--O(CH₂)CH₂ --),7.05 (q,4H,--C₆ H₄ --).

Calculated: C₁₅ H₂₁ NO₃ : C, 66.9; H, 8.42; N, 5.57.

Found: C, 66.9; H, 8.20; N, 5.51.

EXAMPLE XIII Preparation of 2-methyl-4-p-t-butylphenoxy-2-butanol

To a solution of freshly prepared methyl magnesium iodide (from 144 g,1.01 moles, methyl iodide and 54 g, 2.25 moles, magnesium in 700 ml drydiethyl ether) was added a solution of 10.0 g (36.0 mmoles) of the esterbutyl 3-p-t-butylphenoxy propionate in 200 ml diethyl ether. After onehour the reaction mixture was poured over ice/20% H₂ SO₄. The yelloworganic layer was dried and evaporated. The resulting dark oil waschromatographed on 500 g 90 to 200 mesh silica gel (dichloromethaneeluent) yielding an oil which was vacuum distilled (110° C./0.15 mm) toa yellow viscous oil which solidified on cooling,2-methyl-4-p-t-butylphenoxy-2-butanol, 3.1 g.

Analysis: NMR Spectrum (CDCl₃)δ1.27 (s,15H, (CH₃)₃ C--,--C(CH₃)₂ OH),1.93 ##STR22## 4.13 (t,2H,--O--(CH₂)--), 7.05 (q,4H,--C₆ H₄ --).

Calculated: C₁₅ H₂₄ O₂ : C, 75.0; H, 10.0.

Found: C, 75.1; H, 10.1.

EXAMPLE XIV Preparation of 3-p-t-butylphenoxypropyl nicotinatehydrochloride

Nicotinyl chloride was prepared by treating 3.0 g, 8.3 mmoles, nicotinicacid with 10.0 ml thionyl chloride at reflux for two hours. The excessthionyl chloride was distilled and the crystalline acid chloridesuspended in 25 ml dichloromethane. To the stirred slurry was added,dropwise, a solution of 1.0 g (4.5 mmoles) of the alcohol3-p-t-butylphenoxy propanol, in 25 ml dichloromethane. After thirtyminutes the excess acid chloride was quenched, cautiously, with water.The organic layer was removed, dried (MgSO₄), and concentrated to anorange gum. This was dissolved in 25 ml methanol and treated with 10 ml3% methanolic hydrogen chloride. The methanol was evaporated and theresulting white solid recrystallized from hot ethyl acetate yielding theproduct, 3-p-t-butylphenoxypropyl nicotinate hydrochloride, 0.4 g, as awhite crystalline material, m.p. 134° to 136° C.

Analysis: Calculated: C₁₉ H₂₃ NO₃.HCl: C, 65.2; H, 6.92; N, 4.00. Found:C, 65.5; H, 6.89; N, 4.29.

EXAMPLE XV Preparation of 3-p-n-propylphenoxy ethanol

To a well-stirred slurry of 3.9 g sodium hydride (as 50% dispersion inoil) in 300 ml dry dimethyl formamide was added, dropwise, a solution of5.0 g, (36.7 mmoles) p-n-propylphenol in 125 ml dry dimethyl formamide.After the phenoxide had totally formed a solution of 3.5 g, 36.8 mmoles,chloroacetic acid in 50 ml dry dimethyl formamide was added and thesolution was heated to 60° C. for 1.5 hours. The mixture was thenpartitioned between 200 ml toluene and 200 ml 3 N hydrochloric acid. Theorganic layer was removed, washed with water (3×200 ml), dried (MgSO₄)and concentrated to a pale yellow crystalline product. This crystallinematerial was dissolved in 25 ml ice cold dry tetrahydrofuran. To thecold solution was added, dropwise, 33 ml 0.94 molar borane intetrahydrofuran. After two hours the excess borane was destroyed bycareful addition of water. The solution was acidified with 3 Nhydrochloric acid, diluted with 250 ml water, and extracted with 200 mldichloromethane. The organic layer was removed, dried (MgSO₄), andevaporated to a yellow oil which was vacuum distilled (105° C./0.35 mm)to a clear, colorless oil, 3-p-n-propylphenoxy ethanol, 1.0 g.

Analysis: NMR Spectrum (CDCl₃)δ0.93 (t,3H, (CH₃)--CH₂ --), 1.5 (m,2H,CH₃ (CH₂)CH₂ --), 2.52 (t,2H,--CH₂ --(CH₂)--C₆ H₄ --), 3.90(m,4H,--O--(CH₂ --CH₂)OH), 6.93 (q,4H,--C₆ H₄ --).

Calculated: C₁₁ H₁₆ O₂ : C, 73.3; H, 8.95

Found: C, 72.9; H, 9.18.

EXAMPLE XVI Preparation of 4-p-n-propylphenoxy butanol

To a stirred slurry of 2.0 g sodium hydride (as 50% dispersion in oil)in 50 ml dry dimethyl formamide was added dropwise, a solution of 5.0 g(36.8 mmoles) p-n-propylphenol in 50 ml dry dimethyl formamide. Afterthe phenoxide had totally formed a solution of 5.5 g (36.4 mmoles)4-chlorobutyl acetate in 50 ml dry dimethyl formamide was added and thesolution heated at 55° C. for sixteen hours. The mixture was thendiluted with 1 liter water and extracted with 300 ml toluene. Thetoluene was removed, dried and evaporated to a yellow oil. This oil wastreated with 75 ml 1 N methanolic potassium hydroxide at reflux for onehour. The methanol was then distilled and the residue partitionedbetween water/diethyl ether. The ether was separated, dried (MgSO₄) andconcentrated to a yellow oil which was vacuum distilled (110° C./0.10 mmHg) to a clear, colorless oil, 4-p-n-propylphenoxy butanol, 1.7 g.

Analysis: NMR Spectrum (CDCl₃)δ0.93 (t,3H, (CH₃)--CH₂ --), 1.68 (m,6H,CH₂ (CH₂ CH₂)COH+CH₃ (CH₂)CH₂ --), 2.50 (t,2H,--(CH₂)--C₆ H₄ --), 3.64(m,2H, CH₂ --(CH₂)OH), 3.96 (t,2H,--C₆ H₄ --O(CH₂)--), 6.94 (q,4H,--C₆H₄ --).

Calculated: C₁₃ H₂₀ O₂ : C, 75.0; H, 9.68.

Found: C, 75.2; H, 9.72.

EXAMPLES XVII to XXIV Synthesis of 3-(aryloxy)-propanols of Table A

A solution of 1 equivalent of the substituted phenol, 1 equivalent ofsodium hydride, 2.5 equivalents of the acrylate ester andN-phenyl-2-naphthylamine (0.01 mole/1mole phenol) to act as basicpolymerization inhibitor was heated under nitrogen to 115° C. for threehours. The temperature was then reduced to 65° C. and the excessacrylate removed under vacuum. The residue was chromatographed on 90 to200 mesh silica gel yielding the pure 3-phenoxypropionate ester. Theester was dissolved in anhydrous ether and added, cautiously, to astirred slurry of lithium aluminum hydride in anhydrous ether. After onehour the excess hydride was quenched with sodium sulfate decahydrate.The residue was partitioned between water/ethyl acetate. The organiclayer was removed, dried (MgSO₄), and condensed to an oil which wasvacuum distilled to the desired 3-(aryloxy) propanol.

By this procedure the following 3-(aryloxy) propanols were prepared:

                                      TABLE A                                     __________________________________________________________________________    Physical data for 3-(aryloxy)-1-propanols                                                                       % Yield    Theo-                                                                              Theo-                                                         from       retical                                                                            retical                                                                           Actual                                                                             Actual             Example No.                                                                              R.sub.1 *    Boiling point                                                                           Phenol                                                                             Formula                                                                             % C  % H % C  %                  __________________________________________________________________________                                                               H                  XVII       p-CH.sub.3 CH.sub.2 CH.sub.2                                                               119° C./0.15 mm Hg                                                               35.3 C.sub.12 H.sub.18 O.sub.2                                                           74.2 9.34                                                                              73.9 9.38               3-p-n-Propylphenoxy                                                           propanol                                                                      XVIII      p-(CH.sub.2).sub.2 CH                                                                      100° C./0.1 mm Hg                                                                17.1 C.sub.12 H.sub.18 O.sub.2                                                           74.2 9.34                                                                              74.0 9.20               3-p-i-Propylphenoxy                                                           propanol                                                                      XXIX       p-CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                             125° C./0.35 mm Hg                                                               6.5  C.sub.14 H.sub.22 O.sub.2                                                           75.6 9.97                                                                              75.5 9.98               3-p-n-Pentylphenoxy                                                           propanol                                                                      XX         p-CH.sub.3 CH.sub.2 CH(CH.sub.3)                                                           121° C./0.15 mm Hg                                                               34.6 C.sub.13 H.sub.20 O.sub.2                                                           75.0 9.68                                                                              74.5 9.75               3-p-sec-Butylphenoxy                                                          propanol                                                                      XXI        p-(CH.sub.3).sub.2 CHCH.sub.2                                                              110° C./0.10 mm Hg                                                               23.7 C.sub.13 H.sub.20 O.sub.2                                                           75.0 9.68                                                                              74.7 9.61               3-p-i-Butylphenoxy                                                            propanol                                                                      XXII       m-(CH.sub. 3).sub.2 CH                                                                     113° C./0.11 mm Hg                                                               34.7 C.sub.12 H.sub.18 O.sub.2                                                           74.2 9.34                                                                              73.4 9.33               3-m-i-Propylphenoxy                                                           propanol                                                                      XXIII      m-Br         118° C./0.15 mm Hg                                                               15.4 C.sub.9 H.sub.11 O.sub.2 Br                                                         46.78                                                                              4.80                        3-m-BrPhenoxy                                                                 propanol                                                                      XXIV 3-Indanoxy propanol                                                                  ##STR23##   125° C./0.10 mm Hg                                                               14.0 C.sub.12 H.sub.16 O.sub.2                                                           74.97                                                                              8.39                        __________________________________________________________________________     *Formula of Table B                                                      

The following Table correlates the preceding Examples I to XXII with theformula on page 7:

                                      TABLE B                                     __________________________________________________________________________     ##STR24##                                                                    Example No.                                                                          R.sub.1    R.sub.2                                                                             R.sub.3   n.sub.1                                                                          n.sub.2                                                                         n.sub.3                                __________________________________________________________________________    I      t-C.sub.4 H.sub.9                                                                        None  OH        2  0 0                                      II     t-C.sub.4 H.sub.9                                                                        None  OH        3  0 0                                      III    t-C.sub.4 H.sub.9                                                                        None  OH        4  0 0                                      IV     t-C.sub.4 H.sub.9                                                                        None  OH        5  0 0                                      V      t-C.sub.4 H.sub.9                                                                        None  OH        6  0 0                                      VI     t-C.sub.4 H.sub.9                                                                        None  OH        8  0 0                                      VII    t-C.sub.4 H.sub.9                                                                        None  OH        11 0 0                                      VIII*  t-C.sub.4 H.sub.9                                                                        None  OH        5  0 0                                      IX     t-C.sub.4 H.sub.9                                                                        None                                                                                 ##STR25##                                                                              4  0 0                                      X      t-C.sub.4 H.sub.9                                                                        None                                                                                 ##STR26##                                                                              4  0 0                                      XI     t-C.sub.4 H.sub.9                                                                        None                                                                                 ##STR27##                                                                              4  0 0                                      XII    t-C.sub.4 H.sub.9                                                                        None                                                                                 ##STR28##                                                                              3  0 0                                      XIII   t-C.sub.4 H.sub.9                                                                        CH.sub.3 and H                                                                      OH        2  1 0                                      XIV    t-C.sub.4 H.sub.9                                                                        CH.sub.3 and H                                                                       ##STR29##                                                                              3  0 0                                      XV     n-C.sub.3 H.sub.7                                                                        CH.sub.3 and H                                                                      OH        2  0 0                                      XVI    n-C.sub.3 H.sub.7                                                                        CH.sub.3 and H                                                                      OH        4  0 0                                      XVII   n-C.sub.3 H.sub.7                                                                        CH.sub.3 and H                                                                      OH        3  0 0                                      XVIII  iso-C.sub.3 H.sub.7                                                                      CH.sub.3 and H                                                                      OH        3  0 0                                      XIX    n-C.sub.5 H.sub.11                                                                       CH.sub.3 and H                                                                      OH        3  0 0                                      XX     sec-C.sub.4 H.sub.9                                                                      CH.sub.3 and H                                                                      OH        3  0 0                                      XXI    iso-C.sub.4 H.sub.9                                                                      CH.sub.3 and H                                                                      OH        3  0 0                                      XXII   iso-C.sub.3 H.sub.7                                                                      CH.sub.3 and H                                                                      OH        3  0 0                                             (meta)                                                                 XXIII  Br (meta)  None  OH        3  0 0                                      XXIV   indanyl    None  OH        3  0 0                                             (meta)                                                                         ##STR30##                                                             __________________________________________________________________________     ##STR31##                                                                

EXAMPLE XXV Preparation of p-t-butylphenoxybutane:

To a stirred slurry of 4.2 g sodium hydride (as 50% dispersion in oil)in 50 ml dry dimethyl formamide was added, dropwise, a solution of 5.0 g(33.3 mmoles) p-t-butylphenol in 50 ml dry dimethyl formamide. After thephenoxide had totally formed a solution of 9.1 g (66.6 mmoles)n-butylbromide in 50 ml dry dimethyl formamide was added and the mixturestirred for sixteen hours. The reaction mixture was cautiously dilutedwith 200 ml water and extracted with hexane. The organic layer wasremoved, dried (MgSO₄) and concentrated to a yellow oil which was vacuumdistilled (72°/0.8 mm) to a clear, colorless oil, 6.1 g, identified asp-t-butylphenoxybutane.

Analysis: NMR Spectrum (CDCl₃)δ0.95 (t,3H, (CH₃)--CH₂ --), 1.27 (s,9H,(CH₃)₃ C--), 1.63 (m,4H,OCH₃ (CH₂ CH₂)CH₃), 3.93 (t,2H,O--(CH₂)--), 7.07(q,4H,--C₆ H₄ --).

Calculated: C₁₄ H₂₂ O: C, 81.5; H, 10.8.

Found: C, 81.7; H, 10.7.

EXAMPLE XXVI Preparation of p-n-Propylphenoxybutane

To a stirred slurry of 4.2 g sodium hydride (as 50% dispersion in oil)in 50 ml dry dimethyl formamide was added, dropwise, a solution of 5.0 g(36.8 mmoles) p-n-propylphenol in 50 ml dry dimethyl formamide. Afterthe phenoxide had totally formed a solution of 9.0 g (65.9 mmoles)n-butylbromide in 50 ml dry dimethyl formamide and the mixture stirredat room temperature for sixteen hours. The reaction mixture wascautiously diluted with 200 ml water and extracted with hexane. Theorganic layer was dried (MgSO₄) and concentrated to a yellow oil whichwas vacuum distilled (69°/0.225 mm) to a clear, colorless oil, 4.7 gidentified as p-n-propylphenoxybutane.

Analysis: NMR Spectrum (CDCl₃)δ0.93 (m,H H, (CH₃)CH₂ CH₂ --+(CH₃)CH₂ CH₂CH₂ --), 1.57 (m,6H, CH₃ (CH₂ CH₂)CH₂ --O+CH₃ (CH₂)CH₂ --C₆ H₄ --), 2.25(t,2H,--(CH₂)--C₆ H₄ --), 3.91 (t,2H,--O(CH₂)--), 6.91 (q,4H,--C₆ H₄--).

EXAMPLE XXVII Preparation of 3-(p-chlorophenoxy)-lactic acid

A mixture of 1.8 g (14.7 mmoles)3-chlorolactic acid and 3.4 gp-chlorophenol in 15 ml 3.3 N sodium hydroxide was stirred under refluxfor two hours. The mixture was cooled to room temperature and acidifiedto pH=3, with concentrated hydrochloric acid. The resulting whitecrystals were filtered and dissolved in hot water and the hot solutionwas adjusted to pH=1 with concentrated sulfuric acid. Upon cooling theproduct, 3-(p-chlorophenoxy)-lactic acid was collected as clearcrystals, 0.7 g, m.p. 135° to 136° C.; Edelson, et al. Biochem Pharmacol18, 2331 (1969) reported m.p. 137° to 138° C.

EXAMPLE XXVIII Preparation of βmethoxy ethoxy methyl glycolate ester of4-p-t-butylphenoxy-1-butanol

To a solution of 9.0 g (0.1 mole) of methyl glycolate in 150 ml ofacetonitrile is added 24.7 g (0.11 mole) of the triethyl ammonium saltsof methoxy ethoxy methyl chloride and the mixture stirred at reflux forone hour. The solvent is removed in vacuo and the residue is treatedwith 200 ml of toluene. The insoluble salts are removed by filtrationand 22.0 g (0.1 mole) of 4-p-t-butylphenoxy-1-butanol is added to thefiltrate. After addition of 0.24 g (0.005 mole) of sodium hydride as a50% oil dispersion, the mixture is heated to boiling and methanolfractionally distilled until transesterification is complete. Thesolvent is removed in vacuo and the product purified by chromatographyon silica gel.

The effectiveness of the compounds of the invention in inhibiting therelease of mediators from mast cells induced by administration ofcompound 48/80, was evaluated using the procedure described by Lewis andWhittle, British Journal of Pharmacology 61 229 (1977).

EXAMPLES 1 to 14

For purposes of comparision, fourteen compounds of the invention havingthe structure shown in Table I were evaluated against four testcompounds including chlorphenesin and cromolyn sodium, as well as otherstructurally related compounds. The following results were obtained:

                                      TABLE I                                     __________________________________________________________________________     ##STR32##                                                                     Example No.                                                                            R.sub.1                                                                              ##STR33##         30% or morehibiting releaseConcentratio                                      n in-     chlorophenesinrelative                                                       toActivity                                                                            sodiumcromolynrelative                                                       toActivity                  __________________________________________________________________________    Control                                                                       1      Chlorphenesin                                                                          OCH.sub.2.CHOHCH.sub.2 OH                                                                       100      1.0    2.5                                4-chloro                                                               2      4-chloro OCH.sub.2.CHOH.COOH                                                                             Inactive 0      0                           3      3-bromo  OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  Inactive 0      0                           4      Cromolyn sodium                                                                        OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  250      0.4    1.0                         Example                                                                       1      4-n-propyl                                                                             OCH.sub.2.CH.sub.2 OH                                                                           75       1.3    3.3                         2      4-tertiary-butyl                                                                       OCH.sub.2.CH.sub.2 OH                                                                           50       2.0    5.0                         3      3-isopropyl                                                                            OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  75       1.3    3.3                         4      4-isopropyl                                                                            OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  25       4.0    10.0                        5      4-n-propyl                                                                             OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  25       4.0    10.0                        6      4-isobutyl                                                                             OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  Inactive 0      0                           7      4-tertiary-butyl                                                                       OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  10       10.0   25.0                        8      4-sec-butyl                                                                            OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  25       4.0    10.0                        9      4-pentyl OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  25       4.0    10.0                        10     Cyclobutylene                                                                          OCH.sub.2.CH.sub.2.CH.sub.2 OH                                                                  25       4.0    10.0                               (Indane)                                                               11     4-n-propyl                                                                             OCH.sub.2.CH.sub.2.CH.sub.2.CH.sub.2 OH                                                         25       4.0    10.0                        12     4-tertiary-butyl                                                                       OCH.sub.2.CH.sub.2.CH.sub.2.CH.sub.2 OH                                                         10       10.0   25.0                        13     4-n-propyl                                                                             OCH.sub.2.CH.sub.2.CH.sub.2.CH.sub.3                                                            50       2.0    5.0                         14     4-n-propyl                                                                             OCH.sub.2.CH.sub.2C(CH.sub.3).sub.2 OH                                                          50       2.0    5.0                         __________________________________________________________________________

The compounds of the invention were evaluated against cromolyn sodiumand against chlorphenesin by assigning to these controls, respectively,an activity of one, and then representing the activity of the compoundof the invention in comparison thereto as a multiple of one. It isapparent from the results in Table I that the compounds of the inventionare many times more effective than either chlorphenesin or cromolynsodium.

It is interesting to note that the 4-chloro and 3-bromo compounds ofControls 2 and 3 in contrast to chlorphenesin, Control 1, are inactive.This demonstrates that the R₁ substituent must be in the 4- or p-position, and that the COOH group imparts inactivity.

Of the thirteen 4-alkyl compounds tested, Example 7, the compoundcarrying the 4-tertiary-butyl group, was by far the most active. Thisshows that the alkyl group should be highly branched, and preferablytertiary, there being no difference between the 4-isopropyl and4-n-propyl compounds (Examples 4 and 5). Surprisingly, the 4-isobutylcompound (Example 6) is inactive, under these test conditions.

The indane compound (Example 10) shows that the R₁ group can becondensed with the phenyl ring in an alkylene structure, since theindane compound is as effective as the three to five carbon atom alkylcompounds of Examples 5, 6, 8 and 9, having the same alkanol side chain.

The significance of the R₃ hydroxyl group is evident from Example 13,the 4-n-propyl compound in which the alkanol chain hydroxyl group isreplaced by hydrogen. The activity is reduced by half at a doubledconcentration, although the compound is still twice as effective aschlorphenesin.

EXAMPLES 15 to 28

Since the above results demonstrate the greatest effectiveness for thep-tertiary-butyl substituent, a second series of thirteen compounds wereprepared, all p-tertiary-butyl phenoxy ethers having various alkanol oralkanol ester (R₃) substituents, as noted in Table II.

These were tested by the Lewis and Whittle procedure, with the followingresults:

                                      TABLE II                                    __________________________________________________________________________     Example No.                                                                            R.sub.1                                                                              ##STR34##         30% or morehibiting releaseConcentratio                                      n in-     chlorophenesinrelative                                                       toActivity                                                                            sodiumcromolynrelative                                                       toActivity                  __________________________________________________________________________    Example                                                                       15     4-t-C.sub.4 H.sub.9                                                                    OCH.sub.2.CH.sub.2.OH                                                                           50       2.0    5.0                         16     4-t-C.sub.4 H.sub.9                                                                    OCH.sub.2.CH.sub.2.CH.sub.2.OH                                                                  10       10.0   25.0                        17     4-t-C.sub.4 H.sub.9                                                                    OCH.sub.2.CH.sub.2.CH.sub.2.CH.sub.2.OH                                                         10       10.0   25.0                        18     4-t-C.sub.4 H.sub.9                                                                    OCH.sub.2.CH.sub.2.CH.sub.2.CH.sub.2.CH.sub.2.OH                                                10       10.0   25.0                        19     4-t-C.sub.4 H.sub.9                                                                    O(CH.sub.2).sub.6 OH                                                                            5        20.0   50.0                        20     4-t-C.sub.4 H.sub.9                                                                    O(CH.sub.2).sub.8 OH                                                                            5        20.0   50.0                        21     4-t-C.sub.4 H.sub. 9                                                                   O(CH.sub.2).sub.11 OH                                                                           150      0.7    1.7                         22     4-t-C.sub.4 H.sub.9                                                                    OCH.sub.2.CH.sub.2.C(CH.sub.3).sub.2.OH                                                         25       4.0    10.0                        23     4-t-C.sub.4 H.sub.9                                                                    OCH.sub.2.CH.sub.2.CH.sub.2OCONH.sub.2                                                          10       10.0   25.0                        24     4-t-C.sub.4 H.sub.9                                                                    O(CH.sub.3).sub.4OCO.CH.sub.3                                                                   10       10.0   25.0                        25     4-t-C.sub.4 H.sub.9                                                                    O(CH.sub.2).sub.4OCO.O.CH.sub.3                                                                 15       6.7    16.7                        26     4-t-C.sub.4 H.sub.9                                                                     ##STR35##        10       10.0   25.0                        27     4-t-C.sub.4 H.sub.9                                                                     ##STR36##        5        20.0   50.0                        28     4-t-C.sub.4 H.sub.9                                                                     ##STR37##        50       2.0    5.0                         Control                                                                       1      Chlorphenesin                                                                          OCH.sub.2.CHOH.CH.sub.2 OH                                                                      100      1.0    2.5                         2      Chromolyn sodium           250      0.4    1.0                         __________________________________________________________________________

It is interesting to note from Examples 19 to 21 that activity isincreased when the alkanol carbon chain is a straight chain having fromsix to eight carbon atoms. After eight carbon atoms, however, theactivity diminishes markedly, and at eleven carbon atoms the compound isless effective than chlorphenesin.

Example 22 shows that branching in the alkanol chain reduces activity,although the activity is still four times greater than that ofchlorphenesin.

Examples 26 and 27 show a most remarkable enhancing effect on activityupon esterification of the terminal hydroxyl group on the alkanol chainby nicotinic acid. Comparison of Examples 17 and 27 shows that theaddition of the nicotinic acid group doubles the activity. This suggeststhat a compound in which the alkanol chain is from six to eight carbonatoms (as in Examples 19 and 20), if esterified with nicotinic acidwould show an activity of forty times that of chlorphenesin. Similarlyenhanced activities can be postulated by correlating the more activecompounds in Table II with those combining substituents shown in theTable to give an enhanced activity.

The p-alkyl or cycloalkyl phenoxy alkanol ester can be administered tothe animal by any available route, including oral and parenteral(intravenous, intraperitoneal, subcutaneous, and intramuscular)administration or by inhalation. The amount administered is sufficientto inhibit abnormal tissue reactivity due to specific allergichypersensitivity or due to specific irritants by inhibiting the releaseof chemical mediators responsible for the symptoms of allergic diseases,irritation and inflammation produced by irritants andinflammation-causing substances. This amount will depend upon thespecies of animal, and the weight of the animal. For example, in humanadministration, a dosage of the alkanol or ester compound within therange from about 2 mg/kg to about 100 mg/kg per day should besufficient. In the treatment of lower test animals, a similar dosagerange is therapeutic. The upper limit of dosage is that imposed by toxicside effects, and can be determined by trial and error for the animal tobe treated, including humans.

To facilitate administration, the p-alkyl or cycloalkyl phenoxy alkanolor ester compound can be provided in composition form, and preferably indosage unit form. While the compound can be administered per se, it isnormally administered in conjunction with a pharmaceutically acceptablecarrier therefor, which dilutes the compound and facilitates handling.The term "pharmaceutically acceptable" means that the carrier (as wellas the resulting composition) is sterile and nontoxic.

The carrier or diluent can be solid, semisolid, or liquid, and can serveas a vehicle, excipient, or medium for the p-alkyl or cycloalkyl phenoxyalkanol or ester compound. Exemplary diluents and carriers includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, mineral oil, cocoa butter, oil of theobroma,alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylenesorbitan monolaurate, methyl- and propyl-hydroxybenzoate, talc ormagnesium stearate. Other agents that can be used for solubilizing ordispersing of compounds of this invention are dimethyl sulfoxide (DMSO),N,N-dimethyl acetamide (DMAC), propylene glycol and the polyoxyethyleneethers of hexitol fatty acid esters, such as sorbitol and mannitolesterified with lauric, stearic, palmitic or oleic acids, condensed withfrom ten to thirty moles of ethylene oxide. A commercially availablematerial is Tween 80, a polyoxyethylene sorbitol oleate, the oleic acidester of sorbitol condensed with twenty moles ethylene oxide per mole ofsorbitol.

For convenience in handling, the p-alkyl or cycloalkyl phenoxy alkanolor ester compound and carrier or diluent can be enclosed or encapsulatedin a capsule, sachet, cachet, gelatin, paper or other container,especially when intended for use in dosage units. The dosage units canfor example take the form of tablets, capsules, suppositories orcachets.

The following Examples illustrate various forms of dosage units in whichthe p-alkyl or cycloalkyl phenoxy alkanol or ester compound can beprepared:

EXAMPLE A

    ______________________________________                                        Tablet formulation  Mg/tablet                                                 ______________________________________                                        p-Alkyl or cycloalkyl phenoxy                                                                     15                                                        alkanol or ester compound                                                     Lactose             86                                                        Corn starch (dried) 45.5                                                      Gelatin             2.5                                                       Magnesium stearate  1.0                                                       ______________________________________                                    

The p-alkyl or cycloalkyl phenoxy alkanol or ester compound is powderedand passed through a mesh sieve and well mixed with the lactose and 30mg of the corn starch, both passed through a sieve.

The mixed powders are massed with a warm gelatin solution prepared bystirring the gelatin in water and heating to form a 10% w/w solution.The mass is granulated by passing through a sieve, and the moistgranules dried at 40° C.

The dried granules are regranulated by passing through a sieve and thebalance of the starch and the magnesium stearate is added and thoroughlymixed.

The granules are compressed to produce tablets each weighing 150 mg.

EXAMPLE B

    ______________________________________                                        Tablet formulation  Mg/tablet                                                 ______________________________________                                        p-Alkyl or cycloalkyl phenoxy                                                                     100                                                       alkanol or ester compound                                                     Lactose             39                                                        Corn starch (dried) 80                                                        Gelatin             4.0                                                       Magnesium stearate  2.0                                                       ______________________________________                                    

The method of preparation is identical with that of Example A exceptthat 60 mg of starch is used in the granulation process and 20 mg duringtabletting.

EXAMPLE C

    ______________________________________                                        Capsule formulation Mg/capsule                                                ______________________________________                                        p-Alkyl or cycloalkyl phenoxy                                                                     250                                                       alkanol or ester compound                                                     Lactose             150                                                       ______________________________________                                    

The p-alkyl or cycloalkyl phenoxy alkanol or ester compound and lactoseare passed through a sieve and the powders well mixed together beforefilling into hard gelatin capsules of suitable size, so that eachcapsule contains 400 mg of mixed powders.

EXAMPLE D

    ______________________________________                                        Suppositories      Mg/suppositories                                           ______________________________________                                        p-Alkyl or cycloalkyl phenoxy                                                                     50                                                        alkanol or ester compound                                                     Oil of Theobroma   950                                                        ______________________________________                                    

The p-alkyl or cycloalkyl phenoxy alkanol or ester compound is powderedand passed through a sieve and triturated with molten oil of theobromaat 45° C. to form a smooth suspension.

The mixture is well stirred and poured into molds, each of nominal 1 gcapacity, to produce suppositories.

EXAMPLE E

    ______________________________________                                        Cachets             Mg/cachet                                                 ______________________________________                                        p-Alkyl or cycloalkyl phenoxy                                                                     100                                                       alkanol or ester compound                                                     Lactose             400                                                       ______________________________________                                    

The p-alkyl or cycloalkyl phenoxy alkanol or ester compound is passedthrough a mesh sieve, mixed with lactose previously sieved and fittedinto cachets of suitable size so that each contains 500 mg.

EXAMPLE F

    ______________________________________                                        Intramuscular injection                                                       (sterile suspension in aqueous vehicle)                                                                    Mg                                               ______________________________________                                        p-Alkyl or cycloalkyl phenoxy                                                                              10                                               alkanol or ester compound                                                     Sodium citrate               5.7                                              Sodium carboxymethylcellulose (low viscosity grade)                                                        2.0                                              Methyl para-hydroxybenzoate  1.5                                              Propyl para-hydroxybenzoate  0.2                                              Water for injection to 1.0 ml                                                 ______________________________________                                    

EXAMPLE G

    ______________________________________                                        Intraperitoneal intraveneous or subcutaneous                                  injection (sterile solution in aqueous carrier                                system)                      Mg                                               ______________________________________                                        p-Alkyl or cycloalkyl phenoxy alkanol or                                                                   15                                               ester compound                                                                Sodium citrate               5.7                                              Sodium carboxymethylcellulose (low viscosity grade)                                                        2.0                                              Methyl para-hydroxybenzoate  1.5                                              Propyl para-hydroxybenzoate  0.2                                              Water for injection to 1.0 ml                                                 ______________________________________                                    

Having regard to the foregoing disclosure, the following is claimed aspatentable and inventive embodiments thereof:
 1. A process for treatinganimals in need of antihistaminic treatment which comprisesadministering to the animal an amount therapeutically effective as anantihistamine of a p-alkyl or cycloalkyl phenoxy alkanol carbamic acidester having the formula: ##STR38## in which: R₁ is an alkyl grouphaving from one to six carbon atoms, or a bivalent cycloalkylene grouphaving from five to seven ring carbon atoms and condensed with thephenyl group at adjacent ring carbons thereof that the cycloalkylene andphenyl rings share in common;R₂ is lower alkyl having from one to threecarbon atoms or hydrogen; n₁, n₂ and n₃ represent the number of CH₂,C(R₂)₂ and CH₂ groups, respectively, and are numbers within the rangefrom 0 to 10; and at least one of n₁, n₂ and n₃ is other than zero.
 2. Aprocess according to claim 1 in which the administration is orally.
 3. Aprocess according to claim 2 which comprises administering in dosageunit form.
 4. A process according to claim 1 in which R₁ is tertiaryalkyl, n₂ and n₃ are zero, and n₁ is from 2 to
 8. 5. A process accordingto claim 1 in which R₁ is tert-butyl.
 6. A process according to claim 1in which R₂ is H.
 7. A process according to claim 1 in which R₁ istert-butyl and R₂ is H.